Gold nanoparticle conjugated Rad6 inhibitor induces cell death in triple negative breast cancer cells by inducing mitochondrial dysfunction and PARP-1 hyperactivation: Synthesis and characterization.

Abstract

UNLABELLED: We recently developed a small molecule inhibitor SMI#9 for Rad6, a protein overexpressed in aggressive breast cancers and involved in DNA damage tolerance. SMI#9 induces cytotoxicity in cancerous cells but spares normal breast cells; however, its therapeutic efficacy is limited by poor solubility. Here we chemically modified SMI#9 to enable its conjugation and hydrolysis from gold nanoparticle (GNP). SMI#9-GNP and parent SMI#9 activities were compared in mesenchymal and basal triple negative breast cancer (TNBC) subtype cells. Whereas SMI#9 is cytotoxic to all TNBC cells, SMI#9-GNP is endocytosed and cytotoxic only in mesenchymal TNBC cells. SMI#9-GNP endocytosis in basal TNBCs is compromised by aggregation. However, when combined with cisplatin, SMI#9-GNP is imported and synergistically increases cisplatin sensitivity. Like SMI#9, SMI#9-GNP spares normal breast cells. The released SMI#9 is active and induces cell death via mitochondrial dysfunction and PARP-1 stabilization/hyperactivation. This work signifies the development of a nanotechnology-based Rad6-targeting therapy for TNBCs. FROM THE CLINICAL EDITOR: Protein Rad6 is overexpressed in breast cancer cells and its blockade may provide a new treatment against 3N breast cancer. The authors conjugated a small molecule inhibitor SMI#9 for Rad6 to gold nanoparticles in this study and showed that this new formulation specifically targeted chemo-resistant breast cancer cells and highlighted the importance of nanotechnology in drug carrier development.

Authors

Haynes, Brittany; Zhang, Yanhua; Liu, Fangchao; Li, Jing; Petit, Sarah; Kothayer, Hend; Bao, Xun; Westwell, Andrew D; Mao, Guangzhao; Shekhar, Malathy P V;

Keywords

  • Breast/ drug effects
  • Breast/ metabolism
  • Breast/ pathology
  • Cell Death/ drug effects
  • Cell Line, Tumor
  • Enzyme Inhibitors/ administration & dosage
  • Enzyme Inhibitors/ chemistry
  • Enzyme Inhibitors/ pharmacology
  • Female
  • Gold/ chemistry
  • Humans
  • Metal Nanoparticles/ chemistry
  • Mitochondria/ drug effects
  • Mitochondria/ metabolism
  • Mitochondria/ pathology
  • Poly (ADP-Ribose) Polymerase-1/ metabolism
  • Triple Negative Breast Neoplasms/ drug therapy
  • Triple Negative Breast Neoplasms/ metabolism
  • Triple Negative Breast Neoplasms/ pathology
  • Ubiquitin-Conjugating Enzymes/ antagonists & inhibitors
  • Ubiquitin-Conjugating Enzymes/ metabolism

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